Multilayer composite vascular access graft

ABSTRACT

A multilayer composite vascular access graft and a method of constructing such a graft are disclosed. The mcVAG has improved performance characteristics, which include desirable handling characteristics such as ease of suturing, kink resistance and the ability to serve as a cannulation route soon after the implant procedure.

BACKGROUND

1. Field of the Invention

This invention relates to prosthetic vascular access grafts. Moreparticularly, this invention relates to multilayer composite vascularaccess grafts and their method of construction.

2. Description of the State of the Art

Vascular access is the method used to access the bloodstream forhemodialysis patients. Hemodialysis removes blood from the body androutes it to an artificial kidney machine where the blood is cleansedand returned to the patient. Hemodialysis patients require easy androutine access to the bloodstream. The most common forms of vascularaccess are an arteriovenous (A/V) fistula, a central venous catheter(CVC) for temporary access and a prosthetic vascular access graft (VAG).The A/V fistula generally takes 1 to 4 months after surgery to develop,and a CVC is generally inserted until the fistula is ready for use. AVAG is a synthetic tube that is implanted under the skin in your arm andconnected to an artery and a vein. The VAG is the most widely usedvascular access device for long term vascular access in the hemodialysispatient, since there are a variety of factors that prevent the use of anA/V fistula. More than 60% of the hemodialysis patients in the UnitedStates have a VAG.

Hemodialysis patients have benefited from high-flow cannulation VAGs fordecades. A primary material used in the construction of a VAG isexpanded polytetrafluoroethylene (ePTFE). The ePTFE graft has become astandard among vascular surgeons due to its high kink-resistance,conformability and biocompatibility. The primary disadvantage of theePTFE graft is that it must be allowed to “mature” for at least twoweeks after the implant procedure to ensure that sufficient tissuein-growth has occurred and, although not necessarily required, it isoften hoped that cell endothelialization has occurred as well. Thismaturation time helps to provide hemostasis, long-term healing abilityand patency to the graft.

Polyurethane VAGs have been introduced into the U.S. marketplace overthe past three years and are beneficial in that they are available forcannulation immediately after implant, are self-sealing, and as aresult, provide rapid post-cannulation hemostasis. There are a number ofdisadvantages with these grafts including undesired handlingcharacteristics that make it difficult for the surgeon to create ananastomosis, particularly with smaller blood vessels. In addition, thehigh elasticity of polyurethane can result in pulling and kinking in theregion of the anastomosis. Accordingly, one of skill in the art in thefield of VAGs would benefit from the introduction of a VAG with improvedperformance characteristics, which include handling characteristics suchas ease of suturing, kink resistance and the ability to serve as acannulation route soon after the implant procedure.

SUMMARY

Multilayer composite vascular access grafts and their methods ofmanufacture are provided. In one embodiment, the multilayer compositevascular access graft comprises a first layer, a second layer in contactwith or positioned at a distance from the first layer to form ahorizontally aligned composite layer, and a conjoining layer disposed onthe composite layer to conjoin the first layer to the second layer. Themultilayer composite vascular access graft can further comprise afiber-reinforced layer disposed on the conjoining layer. In anotherembodiment, the multilayer composite vascular access graft comprises afirst layer, a second layer and a fiber-reinforced layer. The secondlayer is deposited on the first layer, and the second layer is coatedwith a fiber-reinforced layer.

The multilayer composite vascular access graft (mcVAG) has improvedperformance characteristics, which include desirable handlingcharacteristics such as ease of suturing, kink resistance and theability to serve as a cannulation route soon after the implantprocedure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cross-section of a multilayer composite vascularaccess graft (mcVAG) with a conjoined, composite inner layer accordingto one embodiment of the present invention.

FIGS. 2 a-2 c illustrate a method of depositing a conjoining layer inthe construction of a mcVAG with a conjoined, composite inner layeraccording to one embodiment of the present invention.

FIGS. 3 a and 3 b illustrate alternate methods of applying a mask usinga wrapping tape according to embodiments of the present invention.

FIG. 4 illustrates a cross-section of a mcVAG and an alternate method ofapplying a mask using a wrapping fiber according to one embodiment ofthe present invention.

FIGS. 5 a-5 c illustrate a method of coating a portion of a mcVAG with afiber-reinforced layer according to one embodiment of the presentinvention.

FIGS. 6 a and 6 b illustrate the removal of a mask and overlyingmaterials according to one embodiment of the present invention.

FIGS. 7 a and 7 b illustrate a layered mask system according to oneembodiment of the present invention.

FIGS. 8 a and 8 b illustrate a cross-section of a mcVAG according to oneembodiment of the present invention.

DETAILED DESCRIPTION

As discussed in more detail below, the invention generally includes amultilayer composite vascular access graft (mcVAG) and a method ofconstructing such a graft. The mcVAG includes a combination of materialsthat differ in their physical characteristics. The resulting vascularaccess graft has improved performance characteristics, which includedesirable handling characteristics such as ease of suturing, kinkresistance and the ability to serve as a cannulation route soon afterthe implant procedure.

FIG. 1 illustrates a cross-section of a mcVAG with a conjoined,composite inner layer according to one embodiment of the presentinvention. In this embodiment, the mcVAG can be constructed according toany desired dimension and conformation and comprises a first inner layercomponent 101; a second inner layer component 102; a conjoining layer103; an inner lumen 104; and, an optional fiber-reinforced layer 105.The first and second inner layer components 101 and 102 form what willbe referred to as “a composite inner layer,” which may comprise anycombination of components 101 and 102 and can be arranged in any order.The term “composite inner layer 102, 101, 102” will be used to refer toany variation of these components in a composite inner layer, including,for example, (i) a mcVAG with a composite inner layer 102, 101, whichwould have a first inner layer component 101 and a second inner layercomponent 102 at only one end of the mcVAG; and, (ii) a mcVAG with acomposite inner layer 102, 101, 102, which would have a first innerlayer component 101 and a second inner layer component 102 at each endof the mcVAG.

The structural dimensions of the mcVAG can vary within the range ofdimensions known to be useful to one of skill in the art. In someembodiments, the inner layer components 101 and 102, conjoining layer103 and optional fiber-reinforced layer 105 can be uniform in thicknessor variable in thickness throughout the layer. In other embodiments, awall thickness 106 for first inner layer component 101 and the secondinner layer component 102 can range from about 0.1 millimeter to about1.0 millimeter, or any range therein. In another embodiment, the innerlumen 104 can have an inner diameter ranging from about 1.0 millimeterto about 30 millimeters, or any range therein. In one example, the innerlumen 104 can have an inner diameter ranging from about 5.0 millimetersto about 6.0 millimeters. In another embodiment, the length of thecomposite inner layer 102, 101, 102 can range from about 1.0 centimetersto about 100 centimeters, or any range therein. In one example, thelength of the composite inner layer 102, 101, 102 can range from about20 centimeters to about 50 centimeters. In another embodiment, there isa second inner layer component 102 at each end of the mcVAG, and thelengths of the second inner layer components are not equal.

It should be appreciated that the mcVAG can be comprised of any numberof layers and that each layer of the mcVAG can be formed by any methodknown to one of skill in the art. Each layer of the present inventioncan be either porous or non-porous. In one embodiment, the compositeinner layer 102, 101, 102 can be porous and the conjoining layer 103 canbe non-porous. In another embodiment, the composite inner layer 102,101, 102 can be porous; the conjoining layer 103 can be non-porous; and,the fiber-reinforced layer 105 can be porous. In another embodiment, thecomposite inner layer 102, 101, 102 can be porous; the conjoining layer103 can be non-porous; and, the fiber-reinforced layer 105 can benon-porous. In some embodiments, the layers are formed by coating orextrusion. Any method of coating can be used in practicing the presentinvention including, but not limited to, spraying, dipping, brushing,pouring, spinning, roller coating, meniscus coating, powder coating andvarious inking approaches such as inkjet-type application. In someembodiments, the method of coating is spraying. In other embodiments,the method of coating is dipping. A dipping method is taught in U.S.Pat. No. 4,409,172.

Casting solvents may be required in the formation of each layer of themcVAG. A casting solvent can be a liquid medium within which a desiredsolid material can be solubilized for application. The casting solventmust be carefully selected to avoid adversely affecting an underlyingmaterial such as, for example, the underlying first inner layer 101 andsecond inner layer 102. An underlying material should not be adverselyaffected where it is reasonably insoluble in a casting solvent used toapply an overlying layer. For purposes of the present invention, amaterial is reasonably insoluble in a casting solvent when, despite somesolubility of the material in the solvent during casting, the productcan still be used for its intended purpose. It should be appreciated,however, that the contact between layers can include an integration ofan overlying layer with the underlying layer. The integration involves areduction or elimination of the line of demarcation between layerswithout adversely affecting either layer. Casting solvents can beselected to achieve an integration of layers.

The casting solvent may be chosen based on several criteria including,for example, its polarity, molecular weight, biocompatibility,reactivity and purity. Other physical characteristics of the castingsolvent may also be taken into account, including the solubility limitof the conjoining layer 103 in the casting solvent; oxygen and othergases in the casting solvent; the viscosity and vapor pressure of thecombined casting solvent and conjoining layer 103; the ability of thecasting solvent to diffuse through an underlying material; and thethermal stability of the casting solvent. One of skill in the art hasaccess to scientific literature and data regarding the solubility of awide variety of polymers. Furthermore, one of skill in the art willappreciate that the choice of casting solvent may begin empirically bycalculating the Gibb's free energy of dissolution using availablethermodynamic data. It should be appreciated that the curing process mayaffect the chemical structure of the underlying materials and, thus,their solubility in the casting solvent. It should also be appreciatedthat the kinetics of dissolution are also a factor to consider whenselecting the casting solvent, because a slow dissolution of a materialmay not affect the performance characteristics of a product due to arelatively fast processing time. Exemplary casting solvents for use inthe present invention include, but are not limited to, dimethylacetamide (DMAC) and tetrahydrofuran (THF).

In one example, the materials used to form the first inner layercomponent 101 and the second inner layer component 102 may both besoluble in a highly polar casting solvent such as, for example, water,but may be reasonably insoluble in a lower polarity casting solvent suchas, for example, butanol. In this example, a low polarity castingsolvent can be used for depositing the conjoining layer 103 on thecomposite inner layer 102, 101, 102 without disrupting the structure offirst inner layer component 101 or second inner layer component 102 toan extent great enough to prevent them from being used for theirintended purpose of serving as a composite inner layer 102, 101, 102within a mcVAG.

Each layer can be applied as liquid coating and dried to produce a solidcoating. The drying process may be limited to drying without structuralchemical changes in the material used to form the coating product, andit may also include curing. Regardless, the solid product is arelatively stable and inert material with all its performance propertiesintact. Some materials dry under ambient conditions without the aid ofany additional process conditions. Other materials dry during treatmentwith steam or heating in an oven. Many polyester resins require apost-curing processes, which may include a heating-cooling cycle toincrease the extent of the cure. Examples of process conditions used toproperly dry a material include, but are not limited to, heat,electromagnetic radiation, electron beam, ion or charged particle beam,neutral-atom beam, chemical energy or a combination thereof. Theelectromagnetic radiation may include light and can be broadband orspecific wavelengths. In one embodiment, the drying can occur underambient conditions without additional application of heat,electromagnetic radiation, electron beam, ion or charged particle beam,neutral-atom beam, or chemical energy.

In one embodiment, the first inner layer component 101 can be formed bycoating a mandrel 201 with a polymer or combination of polymers, in aform that is blended, mixed, bonded or connected. For example,polyurethane can be used to form a first inner layer component 101 inthe shape of the mandrel 201. In another embodiment, the second innerlayer component 102 can be formed, for example, using ePTFE andextrusion techniques that are well-known by one of skill in the art.Essentially, an extruded PTFE is expanded to form an ePTFE second innerlayer component 102. Process parameters can be controlled to alter thecharacteristics of the ePTFE, and such process parameters include, butare not limited to, rate of expansion, deformation level, andtemperature. These process parameters can be varied in order to controlstructural features such as, for example, the microporous structure ofthe ePTFE tube. Examples of microporous structural features that affectthe performance characteristics of the mcVAG include, but are notlimited to, fibril orientation and node size. Methods for creating ePTFEtubes with desired characteristics, including multilayer tubes, aretaught in U.S. Pat. No. 6,428,571.

FIGS. 2 a-2 c illustrate a method of depositing a conjoining layer inthe construction of a mcVAG with a conjoined, composite inner layeraccording to one embodiment of the present invention. In FIG. 2 a, thefirst inner layer component 101 is formed on a mandrel 201 by dippingthe mandrel 201 into a vat of first inner layer component 101, dryingfirst inner layer component 101 and trimming first inner layer component101 at both ends to produce clean edges. Examples of materials that maybe used in the formation of the first inner layer component 101 include,but are not limited to, silicones; silicone rubbers; synthetic rubbers;polyethers; polyesters; polyolefins; modified polyolefins such as, forexample, halogenated polyolefins that include, but are not limited to,fluorinated polyolefins; polyamides; fluorinated ethylene propylenecopolymer (FEP); polyfluorinated alkanoate (PFA); polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. Inone embodiment, the first inner layer component 101 can be comprised ofpolyurethane. In another embodiment, the first inner layer component 101can be comprised of Thoralon® (Thoratec Corp.) The two major componentsin Thoralon® are surface modifying additives and BPS-215polyurethaneurea, a high-flex-life elastomer. In any embodiment of thepresent invention, a salt of a polymer can be added for a variety ofreasons such as, for example, to provide solubility, conductivity orreactivity.

It is to be appreciated that a mandrel may not be necessary in theconstruction of a mcVAG of the present invention. However, where amandrel 201 is used, it should be comprised of materials that are notsubstantially altered by the chosen process variables such that themandrel 201 can still be used for its intended purpose. Relevant processvariables include, but are not limited to, choice of casting solventsand methods of drying. Furthermore, the mandrel 201 should not becomprised of a material that will adhere or bond to the first innerlayer component 101 or second inner layer component 102. The mandrel 201can be comprised of any material or a combination of materials known toone of skill in the art to be useful in the formation of polymericlayers. In one embodiment, the mandrel comprises stainless steel. Inanother embodiment, the mandrel comprises glass. In another embodiment,the mandrel comprises wax. The surface properties of the mandrel 201 canalso be chemically or physically altered to produce a desired outcomesuch as, for example, a reduction in surface adhesion or formation of atextured surface on the inner lumen 104.

In FIG. 2 b, the second inner layer components 102 are slipped onto bothends of the mandrel 201 until they communicate with the first innerlayer component 101 to form a composite inner layer 102, 101, 102.Examples of materials that may be used in the formation of the secondinner layer component 102 include, but are not limited to, silicones;silicone rubbers; synthetic rubbers; polyethers; polyesters;polyolefins; modified polyolefins such as, for example, halogenatedpolyolefins that include, but are not limited to, fluorinatedpolyolefins; polyamides; FEP; PFA; polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. Inone embodiment, the second inner layer component 102 can be comprised ofPTFE. In another embodiment, the second inner layer component 102 can becomprised of ePTFE. A common type of PTFE is Teflon® (DuPont, Inc.), andcommon types of ePTFE are Gore-Tex® (W.L. Gore and Assoc., Inc.) andSoftForm® (EZX Corp.). Both PTFE and ePTFE are biologically inert,non-biodegradable, typically softer than implants comprising siliconeand can be manufactured in many forms including, but not limited to,sheets, strands and tubes. The ePTFE is well-suited for a vascularaccess graft because it is a woven mesh-like form of PTFE that isflexible, soft, strong and sufficiently porous to allow for integrationof body tissue within the ePTFE structure. In another embodiment, thereis only one second inner layer component 102. In another embodiment,there is a second inner layer component 102 at each end of the mcVAG,and the lengths of the second inner layer components are not equal.

The communicating between the first inner layer component 101 and thesecond inner layer component 102 includes, but is not limited to,abutting, overlapping or placing in close proximity. In the compositeinner layer 102, 101, 102, the first inner layer component 101communicates with the second inner layer components 102 such that thefirst inner layer component 101 and the second inner layer components102 form an inner lumen 104 that is continuous.

The first inner layer component 101 and the second inner layer component102 are preferably porous. While not intending to be bound by any theoryor mechanism of action, the inner lumen 104 is a blood interface thatcan eventually develop a biologic lining composed of platelets,endothelial-like cells, macrophages and lymphocytes. As a result, theinner lumen 104 can comprise a biologic pseudointima that makes use ofan anticoagulant typically unnecessary. Accordingly, the mcVAG can bedesigned such that the inner lumen 104 has a structure that promotesendothelialization to prevent or inhibit thrombus formation.

Endothelialization can be promoted by creating a porous or rough surfaceon the inner lumen 104. An average pore diameter sufficient to promoteendothelialization can range from 1 micron to about 400 microns, fromabout 2 microns to about 200 microns, from about 4 microns to about 100microns, from about 8 microns to about 80 microns, from about 10 micronsto about 20 microns, or any range therein. In another embodiment, theinner lumen 104 has a rough surface comprising, for example, pits,grooves, flutes, fibrils, protuberances or a combination thereof. Theintersections where fibrils meet are termed “nodes,” and the distancebetween nodes is termed the “internodal distance.” The internodaldistance can range from about 40 microns to about 200 microns, fromabout 50 microns to about 100 microns, from about 60 microns to about 75microns, or any range therein. In some embodiments, nodes are onlypresent in the first inner layer component 101.

Porosity can be introduced into the layers of the present invention byany method known to one of skill in the art. In one embodiment, theporosity can be introduced into the layers by adding particles to thematerials used to form the layers. For example, the first inner layercomponent 101 and second inner layer component 102 can be made porous byadding particles to the material, forming the layer, and then removingthe particles to create porous structures. In some embodiments, theporous structure is present only in the first inner layer component 101.Pore size can be controlled by screening the particles according to sizeand adding particles of a predetermined size to the materials. Theparticles may include, but are not limited to, salts and water-solublepolymers. In some embodiments, water-soluble polymers include, forexample, polymeric salts, polyvinyl alcohol, polyethylene glycol,polyethylene oxide, dextran, and combinations thereof. Such particlesmay be removed, for example, by washing in water or a very dilute acidbath. Examples of non-polymeric salts include, but are not limited to,NaCl and sodium bicarbonate (bicarb). In other embodiments, the methodsof forming the porous structure include stretching the first inner layercomponent 101 and the second inner layer component 102 to induceformation of pores or voids in the material. In one example, the firstinner layer component 101 and the second inner layer component 102 canbe formed to a predetermined smaller size and stretched to a necessarydimension. In other embodiments, the methods of forming the porousstructure include precipitation of a cast polymer solution in an aqueousliquid such as, for example, water, prior to curing. In otherembodiments, the methods of forming the porous structure includepressuring and sintering a powder of a polymer such as, for example,PTFE to form a film with internal bridging that may be stretched tocontrol the size of the pore structure created; and, bombardment of apolymer film with high-energy particles followed by chemical etching tocreate a pore structure.

In some embodiments, a layer is “porous” when it has a void-to-volumepercentage that ranges from about 40% to about 90%, from about 70% toabout 80%, or any range therein. In some embodiments, a layer is“non-porous” when it has a void-to-volume percentage that ranges fromabout 0% to about 5%, from about 1% to about 3%, and any range therein.The “void-to-volume percentage” is defined as the volume of the poresdivided by the total volume of the layer including the volume of thepores. In some embodiments, the void-to-volume percentage can bemeasured using standard test method BSR/AAMI/ISO 7198, which has beenadopted in-whole as a revision of ANSI/AAMI VP20-1994 (CardiovascularImplants—Vascular Prosthesis section 8.2.1.2, Method for GravimetricDetermination of Porosity, Am. Nat'l Stds. Inst./Assoc. for the Adv. ofMed. Instr.)

The layers of the mcVAG may also be at least partially coated with anantiplatelet, anticoagulant, antifibrin, antithrombin, or a combinationthereof, to prevent or inhibit thrombus formation. Examples ofantiplatelets, anticoagulants, antifibrins and antithrombins include,but are not limited to, albumin, gelatin, glycoproteins, heparin,hirudin, recombinant hirudin, argatroban, forskolin, vapiprost,prostacyclin, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, platelet receptor antagonist glycoproteinIIb/IIIa antibodies such as 7E-3B, thrombin inhibitors such as ANGIOMAX(Biogen, Inc.), and any analogs, homologues, congeners, derivatives,salts and combinations thereof.

In some embodiments, the inner lumen 104 can act as a scaffolding forhost cells comprising nucleic acids encoding for polypeptides that areantithrombogenic. In another embodiment, the inner lumen 104 can besurface-modified with polyethylene glycol (PEG). For example, aPEG-diisocyanate with a molecular weight of about 3400 daltons maypotentially react with protein amines to form molecular barriers onadsorbed proteins on inner lumen 104 to prevent or inhibit theattachment of adhesive ligands and formation of acute surfacethrombosis. In other embodiments, surface treatments including, but notlimited to, plasma treatment, corona discharge, flame treatment, thermaltreatment, chromic acid etching, and sodium treatment may be used tocontrol surface properties such as, for example, the surface tension orreactivity of a polymer surface and to potentially introduce functionalgroups such as, for example, hydroxyl, carbonyl, carboxyl, sulfoxyl,aldehyde, hydroperoxide, ether, ester, amino and amido groups.

In FIG. 2 c, the conjoining layer 103 is deposited on a segment of thecomposite inner layer 102, 101, 102. A mask 202 is applied on the secondinner layer components 102 such that portions 203 of the second innerlayer components 102 are left unmasked in preparation for depositing theconjoining layer 103 on the composite inner layer 102, 101, 102. Theconjoining layer 103 is then deposited on the masked composite innerlayer 102, 101, 102 to conjoin the first inner layer component 101 tothe second inner layer components 102 and form an inner lumen 104 thatis continuous and sealed. In one embodiment, the portions 203 can rangefrom about 0.05 inches to about 12 inches in length, from about 0.1inches to about 6 inches in length, from about 0.2 inches to about 3inches in length, from about 0.25 inches to about 0.75 inch in length,or any range therein.

The method used for depositing the conjoining layer 103 on the compositeinner layer 102, 101, 102 depends on whether conjoining layer 103 waspreformed prior to the depositing. As described above, the conjoininglayer 103 can be preformed, for example, through an extrusion process oron a mandrel 201, or it can be applied directly as a liquid coating onthe composite inner layer 103. In one embodiment, the conjoining layer103 can be a preformed tubular material that is expanded and placed on acomposite inner layer 102, 101, 102 on a mandrel 201. In anotherembodiment, the conjoining layer 103 can be a liquid that is sprayed ona composite inner layer 102, 101, 102 on a mandrel 201 and dried underambient conditions. In another embodiment, the composite inner layer102, 101, 102 can be dipped into a vat of liquid conjoining layer 103,and the conjoining layer 103 can be dried with any method describedabove.

The mask 202 should be comprised of a material that is reasonablyinsoluble in the casting solvent used to deposit the conjoining layer103. In some embodiments, the mask 202 can be easily removed with asolvent that will not adversely affect other materials in the mcVAG.These embodiments may require the use of such a solvent, because themask 202 can sometimes unavoidably adhere to the composite inner layer102, 101, 102. For example, if the casting solvent used to deposit theconjoining layer 103 is DMAC, then the mask 202 should be reasonablyinsoluble in DMAC. Likewise, if the casting solvent is THF, then themask 202 should be reasonably insoluble in THF. In one embodiment, themask 202 can be a layer of salt that was applied to the composite innerlayer 102, 101, 102 as a supersaturated solution. A variety of salts maybe used as the mask 202 and removed with either water or a weak acid. Inone example, the mask 202 comprises NaCl, which may be easily removedwith water after depositing the conjoining layer 103 and is reasonablyinsoluble in a DMAC casting solvent. In another embodiment, the mask 202can be made from a water-soluble polymer. In some embodiments,water-soluble polymers may include, for example, polymeric salts,polyvinyl alcohol, polyethylene glycol, polyethylene oxide, dextran, andcombinations thereof. In another embodiment, the mask 202 can be madefrom a material that may not be easily removable by a solvent and, thus,requires removal by applying force without additional application of asolvent. Examples of such masks 202 include, but are not limited to,metals and metal alloys such as, for example, aluminum, stainless steel,gold, cured silicone, and the like.

FIGS. 3 a and 3 b illustrate alternate methods of applying a mask usinga wrapping tape according to embodiments of the present invention. InFIG. 3 a, a masking wrap 301 is applied as a wrapping tape around thesecond inner layer component 102 such that it overlaps tightly uponitself in order to avoid penetration of the masking wrap 301 by theconjoining layer 103. In FIG. 3 b, a masking wrap 301 is applied as asingle wrap.

FIG. 4 illustrates a cross-section of a mcVAG and an alternate method ofapplying a mask using a wrapping fiber according to one embodiment ofthe present invention. The masking wrap 301 is wrapped around the secondinner layer component 102 such that it is positioned tightly againstitself in order to avoid penetration of the masking wrap 301 by theconjoining layer 103. The materials composing the masking wrap 301 maybe selected as described above for the mask 202. In some embodiments,the masking wrap 301 can be a stainless steel foil. In otherembodiments, the masking wrap 301 can be a stainless steel wire. In oneembodiment, the stainless steel foil can range from about 0.001 inchesthick to about 0.020 inches thick, from about 0.002 inches thick toabout 0.01 inches thick, from about 0.003 inches thick to about 0.007inches thick, or any range therein. In another embodiment, the stainlesssteel wire can range from about 0.001 inches thick to about 0.020 inchesthick, from about 0.003 inches thick to about 0.012 inches thick, fromabout 0.006 inches thick to about 0.010 inches thick, or any rangetherein.

FIGS. 5 a-5 c illustrate a method of coating a portion of a mcVAG with afiber-reinforced layer according to one embodiment of the presentinvention. The fiber-reinforced layer 105 provides enhanced kinkresistance. In FIG. 5 a, the method of coating comprises applying a foammaterial 502 to an underlying material 501 such as, for example, theconjoining layer 103. In FIG. 5 b, the method further comprises placinga fiber layer 503 on the foam layer 502. In FIG. 5 c, the method furthercomprises applying an additional foam layer 504 on the fiber layer 503to form a mcVAG with a fiber reinforced layer. The foam layers 502, 504can be applied using any method of forming a layer described herein andknown to one of skill in the art. The fiber layer 503 can be wrappedonto the foam layer 502; preformed and slipped onto the foam layer 502;preformed and crimped onto the foam layer 502; or applied by any methodknown to one of skill in the art. The steps of applying the foam layer502, placing a fiber layer 503 and applying an additional foam layer 504can be repeated to form additional layers of fiber and foam for astronger fiber-reinforced layer 105 with an even greater kinkresistance. It should be appreciated that the fiber-reinforced layer maybe formed from a non-foam material.

The conjoining layer 103 and the fiber-reinforced layer 110 can beindependently formed from the same or different materials. Examples ofmaterials that may be used to form the conjoining layer 103 and thefiber-reinforced layer 105 include, but are not limited to, silicones;silicone rubbers; synthetic rubbers; polyethers; polyesters;polyolefins; modified polyolefins such as, for example, halogenatedpolyolefins that include, but are not limited to, fluorinatedpolyolefins; polyamides; FEP; PFA; polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. Inone embodiment, the conjoining layer 103 and the fiber-reinforced layer105 may be independently comprised of polyurethane. In anotherembodiment, the conjoining layer 103 and the fiber-reinforced layer 105may be independently comprised of Thoralon®.

In some embodiments, the conjoining layer 103 and the fiber-reinforcedlayer 105 may also include a gel. Examples of gels that may be used inthe present invention include, but are not limited to, gelatin,collagen, albumin, casein, algin, carboxy methyl cellulose, carageenan,furcellaran, agarose, guar, locust bean gum, gum arabic, hydroxyethylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyalkylmethylcellulose, pectin, partially deacetylated chitosan, starch and starchderivatives, including amylose and amylopectin, xanthan, polylysine,hyaluronic acid, heparin and any analogs, homologues, congeners,derivatives, salts and combinations thereof. In some embodiments, thegel can be a hydrogel.

The fiber layer 503 can be comprised of any material suitable forincorporation into a layer that is designed to provide kink-resistanceto the mcVAG. Examples of suitable materials for use in the fiber layer503 include, but are not limited to, metals, alloys, polymers andcombinations thereof. Examples of metals and metal alloys include, butare not limited to, ELASTINITE® (Guidant Corp.), NITINOL (NitinolDevices and Components), stainless steel, tantalum, tantalum-basedalloys, nickel-titanium alloy, platinum, platinum-based alloys such as,for example, platinum-iridium alloys, iridium, gold, magnesium,titanium, titanium-based alloys, zirconium-based alloys, alloyscomprising cobalt and chromium (ELGILOY®, Elgiloy Specialty Metals,Inc.; MP35N and MP20N, SPS Technologies), and combinations thereof. Thetradenames “MP35N” and “MP20N” describe alloys of cobalt, nickel,chromium and molybdenum. The MP35N consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. The MP20N consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Examples of polymers include,but are not limited to, segmented-polyurethanes and other segmented orblock copolymers with similar structural properties. Examples ofsegmented-polyurethanes include, but are not limited to, polyetherurethane ureas, polyether urethanes and polyester urethanes. Whilesegmented polyurethanes are highly effective base polymers for use inthe present invention, other segmented or block copolymers with similarstructural properties may also be used. Examples of other segmented orblock copolymers include, but are not limited to, polyester-polyethers,polyesters, polyether-polyamides, polyamides (e.g. nylon),styrene-isoprenes, styrene butadienes, thermoplastic polyolefins,styrene-saturated olefins, polyester-polyester, ethylene-vinyl acetate,ethylene-ethyl acrylate, ionomers, thermoplastic polydienes. Reinforcedrubbers may be used where the reinforcement serves the same purpose asthe hard block in the segmented copolymer. In one embodiment, the fibermaterial comprises a polyester such as, for example, Dacron® (EI du Pontde Nemours and Co., Inc.) or Hytrel® (EI du Pont de Nemours and Co.,Inc.). In another embodiment, the fiber comprises a polyamide and,preferably, the polyamide is Nylon® (EI du Pont de Nemours and Co.,Inc.) In another embodiment, the fiber material comprises a metal ormetal alloy. In one example, the fiber is low-ferromagnetic. In anotherexample, the fiber is non-ferromagnetic. In another example, the fibercomprises stainless steel.

In one embodiment, the tensile strength of the fiber material should bein the range of from about 2500 psi to about 2,500,000 psi, from about10,000 psi to about 2,500,000 psi, from about 50,000 psi to about100,000 psi, or any range therein. In some embodiments, a wound fiberlayer can have a pitch in the range of from about 1 to about 10, fromabout 1.5 to about 7.5, from about 2 to about 6, or any range therein.“Pitch” is a measure of the ratio of the distance between the spiralloops to diameter of the fiber.

FIGS. 6 a and 6 b illustrate the removal of a mask and overlyingmaterials according to one embodiment of the present invention. The mask202 and any overlying materials such as, for example, a portion 601 ofthe conjoining layer 103 and a portion 602 of the fiber-reinforced layer105, are removed to expose an underlying bare portion 603 of the secondinner layer component 102. In one embodiment, the underlying bareportion 603 can be ePTFE. In one embodiment, there is only one secondinner layer component 102. In another embodiment, there is a secondinner layer component 102 at each end of the mcVAG, and the lengths ofthe second inner layer components are not equal.

In FIG. 6 a, removing the mask comprises making a circumferential cut604 to a depth of the outermost surface of the mask 202 and through anyoverlying materials 601, 602 at a position such that the length 605 ofthe mask 202 exceeds the length 606 of the overlying materials 601, 602.In FIG. 6 b, the mask 202 and overlying materials 601, 602 are removedto create an overhang 607. The overhang 607 defines a circumferentialspace between the conjoining layer 103 and the second inner layer 102and covers rough edges that may be created from removing the mask 202and the overlying materials 601, 602 from the mcVAG. It is to beappreciated that the overhang 607 is optional. In some embodiments,there is no overhang 607. In other embodiments, the overhang 607 isminimized. In one embodiment, the overhang 607 ranges from about 0.01inches to about 0.25 inches in length, from about 0.03 inches to about0.20 inches in length, from about 0.05 inches to about 0.15 inches inlength, from about 0.07 inches to about 0.12 inches in length, or anyrange therein.

FIGS. 7 a and 7 b illustrate a layered mask system according to oneembodiment of the present invention. In some embodiments, the use of asingle mask 202 can increase the diameter of a mcVAG during itsformation to a size greater than the orifice needed in a next dippingstep of the formation process. Accordingly, a system that avoids such adiametrical constraint would be beneficial. In FIG. 7 a, a first mask701 is removed with overlying material 601 as described above in FIG. 6after depositing the conjoining layer 103. In FIG. 7 b, a second mask702 is applied to the second inner layer component 102. A coating of afiber-reinforced layer 105 is then applied to the second mask 702 andthe conjoining layer 103. The second mask 702 is removed with overlyingmaterial 602 as described above in FIG. 6 after depositing thefiber-reinforced layer 105 to produce a mcVAG with a fiber-reinforcedlayer and an overhang 607, as described above. Each mask used in thelayered masking system is removed with overlying layers formed duringconstruction of the mcVAG and replaced by another mask when necessary toprevent an excessive buildup of layers that would otherwise increase thediameter of the mcVAG to a size greater than the next size orifice usedin the dipping process.

It should be appreciated that a mask 202 may not have to be in directcontact with the composite inner layer 102, 101, 102 in coatingapplications that are precise. For example, in some embodiments usingspray coating methods, the mask can be placed between the compositeinner layer 102, 101, 102 and the source of the spray. Furthermore, whena spray is sufficiently precise, a mask 202 may be unnecessary tomaintain bare portion 603 during formation of each of the layers in themcVAG.

FIGS. 8 a and 8 b illustrate a cross-section of a mcVAG according to oneembodiment of the present invention. In FIG. 8 a, a mcVAG having asingle inner layer comprises a first layer 801, a second layer 802, anda fiber-reinforced layer 803. The method of constructing a mcVAG with asingle inner layer comprises depositing the second layer 802 on acentral portion 806 of the first layer 801 and coating the second layer802 with the fiber-reinforced layer 803 to complete construction of amultilayer composite vascular access graft. Methods of forming thelayers and optional methods for applying and removing a mask 805 aredescribed above and generally comprise making a circumferential cut 807through overlying materials 802, 803. In FIG. 8 b, the mask 805 andoverlying materials 802, 803 are removed to expose a portion 808 offirst layer 801 with a slight overhang 809. It should be appreciatedthat the mcVAG can be comprised of any number of layers and that eachlayer of the mcVAG can be formed by any method known to one of skill inthe art. Each layer of the present invention can be porous ornon-porous. In one embodiment, the bare portion 808 is only at one endof the mcVAG. In another embodiment, there is a bare portion 808 at eachof the mcVAG, and the lengths of the bare portions 808 are not equal.

Examples of materials that may be used to form the first layer 801include, but are not limited to, silicones; silicone rubbers; syntheticrubbers; polyethers; polyesters; polyolefins; modified polyolefins suchas, for example, halogenated polyolefins that include, but are notlimited to, fluorinated polyolefins; polyamides; FEP; PFA;polyurethanes; segmented-polyurethanes; segmentedpolyether-polyurethanes; polyurethaneurea; silicone-polyurethanecopolymers; and, any analogs, homologues, congeners, derivatives, saltsand combinations thereof. In one embodiment, the first layer 801 can becomprised of PTFE. In another embodiment, the first layer 801 can becomprised of ePTFE. In another embodiment, the first layer 801 can beporous, and the porous structure of the first can be obtained by themethods described above.

Examples of materials that may be used to form the second layer 802 orthe fiber-reinforced layer 803 include, but are not limited to,silicones; silicone rubbers; synthetic rubbers; polyethers; polyesters;polyolefins; modified polyolefins such as, for example, halogenatedpolyolefins that include, but are not limited to, fluorinatedpolyolefins; polyamides; FEP; PFA; polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. Inone embodiment, the second layer 802 or the fiber-reinforced layer 803can be comprised of polyurethane. In another embodiment, the secondlayer 802 or the fiber-reinforced layer 803 can be comprised ofThoralon®. In another embodiment, the second layer 802 or thefiber-reinforced layer 803 can be comprised of a gel, and examples ofgels are described above.

The inner lumen 804 can be designed to promote endothelialization forprevention or inhibition of thrombus formation. As described above,inner lumen 804 can be porous or rough to promote endothelialization; atleast partially coated with an antiplatelet, anticoagulant, antifibrin,antithrombin to prevent or inhibit thrombus formation; and treated inother ways to prevent or inhibit thrombus formation. Other ways to treatinner lumen 804 include, but are not limited to, designing the innerlumen 804 to act as a scaffolding for host cells that secretepolypeptides that are antithrombogenic and modifying the surface of theinner lumen 804 with, for example, polyethylene glycol.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

1. A multilayer composite vascular access graft comprising a firstlayer; a second layer in contact with or positioned at a distance fromthe first layer to form a horizontally aligned composite layer; and aconjoining layer disposed on the composite layer to conjoin the firstlayer to the second layer within a multilayer composite vascular accessgraft.
 2. The multilayer composite vascular access graft of claim 1,further comprising a fiber-reinforced layer disposed on the conjoininglayer.
 3. The multilayer composite vascular access graft of claim 1,wherein the conjoining layer covers the first layer and a segment of thesecond layer such that a portion of the second inner layer is exposed.4. The multilayer composite vascular access graft of claim 3, whereinthe conjoining layer includes an overhang portion disposed over thesecond layer.
 5. The multilayer composite vascular access graft of claim1, wherein the first layer is porous.
 6. The multilayer compositevascular access graft of claim 1, wherein the first layer comprises amaterial selected from the group consisting of silicones; siliconerubbers; synthetic rubbers; polyethers; polyesters; polyolefins;modified polyolefins; polyamides; fluorinated ethylene propylenecopolymer (FEP); polyfluorinated alkanoate (PFA); polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. 7.The multilayer composite vascular access graft of claim 1, wherein thefirst layer comprises polyurethane.
 8. The multilayer composite vascularaccess graft of claim 1, wherein the first layer comprises BPS-215polyurethaneurea or Thoralon®.
 9. The multilayer composite vascularaccess graft of claim 1, wherein the second layer comprises expandedpolytetrafluoroethylene (ePTFE).
 10. The multilayer composite vascularaccess graft of claim 1, wherein the conjoining layer is non-porous. 11.The multilayer composite vascular access graft of claim 1, wherein theconjoining layer comprises a material selected from the group consistingof silicones; silicone rubbers; synthetic rubbers; polyethers;polyesters; polyolefins; modified polyolefins; polyamides; FEP; PFA;polyurethanes; segmented-polyurethanes; segmentedpolyether-polyurethanes; polyurethaneurea; silicone-polyurethanecopolymers; and, any analogs, homologues, congeners, derivatives, saltsand combinations thereof.
 12. The multilayer composite vascular accessgraft of claim 1, wherein the conjoining layer comprises polyurethane.13. The multilayer composite vascular access graft of claim 1, whereinthe conjoining layer comprises polyurethaneurea or Thoralon®.
 14. Themultilayer composite vascular access graft of claim 1, wherein theconjoining layer comprises a gel.
 15. The multilayer composite vascularaccess graft of claim 2, wherein the fiber-reinforced layer comprises amaterial selected from the group consisting of silicones; siliconerubbers; synthetic rubbers; polyethers; polyesters; polyolefins;modified polyolefins; polyamides; FEP; PFA; polyurethanes;segmented-polyurethanes; segmented polyether-polyurethanes;polyurethaneurea; silicone-polyurethane copolymers; and, any analogs,homologues, congeners, derivatives, salts and combinations thereof. 16.The multilayer composite vascular access graft of claim 2, wherein thefiber-reinforced layer comprises a material selected from a groupconsisting of polyurethane, polyester, BPS-215 polyurethaneurea, orThoralon®.
 17. The multilayer composite vascular access graft of claim1, wherein the multilayer composite vascular access graft is at leastpartially coated with an antithrombin agent.
 18. A multilayer compositevascular access graft comprising a first layer, a second layer and afiber-reinforced layer, wherein the second layer is deposited on thefirst layer, and the second layer is coated with a fiber-reinforcedlayer within a multilayer composite vascular access graft.
 19. Themultilayer composite vascular access graft of claim 18, wherein thesecond layer covers only a segment of the first layer, and the secondlayer includes an overhang so as to provide a circumferential spacebetween the overhang and the first layer.
 20. A method of constructing amultilayer composite vascular access graft comprising: setting a firstlayer; setting a second layer in contact with or at a distance from thefirst layer; positioning a mask over a segment of the second layer suchthat a portion of the second layer is not covered by the mask; setting athird layer over the first and second layers, wherein the mask preventsthe third layer from being deposited on the segment of the second layer;removing the mask to expose the segment of the second layer covered bythe mask.
 21. The method of claim 20, wherein removal of the maskcomprises forming a cut through the third layer at least to a surface ofthe mask followed by removal of the mask.
 22. The method of claim 20,further comprising setting a fourth layer on the third layer prior toremoval of the mask.
 23. The method of claim 21, wherein removal of themask comprises forming a cut through the fourth layer at least to asurface of the mask followed by removal of the mask.
 24. The method ofclaim 22, wherein the fourth layer is a fiber reinforced layer.
 25. Themethod of claim 20, additionally comprising, subsequent to the removalof the mask, positioning a second mask over the second layer; forming afourth layer on the third layer, wherein the mask prevents the fourthlayer from being deposited on the second layer; and removing the secondmask.
 26. The method of claim 25, wherein the fourth layer is a fiberreinforced layer.
 27. The method of claim 20, wherein the first andsecond layers are porous and the third layer is non-porous.
 28. A methodof constructing a multilayer composite vascular access graft comprising:setting a first layer; positioning a mask over a segment of the firstlayer; setting a second layer over the first layer such that the maskprotects the segment of the first layer from the second layer; andremoving the mask to expose the segment of the first layer covered bythe mask.
 29. The method of claim 28, additionally comprising depositinga third layer prior to removal of the mask.
 30. The method of claim 28,wherein the third layer is a fiber-reinforced layer.
 31. The method ofclaim 29, wherein removal of the mask comprises forming a cut throughthe third layer at least to a surface of the mask followed by removal ofthe mask.
 32. The method of claim 27, additionally comprising,subsequent to removal of the mask positioning a second mask on theexposed first layer; setting a third layer on the second layer such thatthe mask protects the first layer from the third layer; and removing themask to expose the segment of the first layer covered by the mask. 33.The method of claim 28, wherein the first layer includes a firstsub-layer in contact with or positioned next to a second sub-layer,wherein the segment of the first layer covered by the mask includes aportion of the second-sub-layer.
 34. A method of constructing amultilayer composite vascular access graft comprising: forming a firstlayer; positioning a masking element over a segment of the first layer;forming a second layer on the first layer wherein the mask protects thesegment of the first layer covered by the masking element so as to forma multilayer composite vascular graft structure.
 35. The method of claim34, additionally including removing the masking element to expose thesegment of the first layer protected by the masking element.
 36. Themethod of claim 34, wherein the positioning of the masking elementcomprises: wrapping the masking element on the segment of the firstlayer; depositing a masking material on the segment of the first layer;or positioning the masking element between a depositing apparatus andthe first layer such that the masking element is not in contact with thefirst layer.
 37. The method of claim 34, wherein the first layerincludes a first sub-layer and a second sub-layer positioned in ahorizontal alignment with the first sub-layer such that the maskingelement covers a portion of the second sub-layer.